The goal of this proposal is to efficiently design and synthesize nucleoside analogs as effective inhibitors of the HIV-1 reverse transcriptase enzyme. The specific aims of this project include the following: 1. The development of novel purine and pyrimidine nucleoside analogs that exhibit promising anti-HIV profiles. This includes: a) the synthesis of dioxolane, oxathiolane, and cyclobutyl analogs; b) prodrug development to improve incorporation of the analog into the cell. 2. The development of methodology to improve the N9 vs. N7 regioselectivity of the purine base coupling. These efforts will include the following: a) selective substitution on position 6 of the purine with bulky trialkyl silane derivatives; b) regioselective coupling between the silylated base and the-sugar analog; c) effective substitution of the silyl group on the coupled analog to create a series of derivatives. Though there is not yet a cure for the acquired immune deficiency syndrome (AIDS), there are agents that dramatically increase the lifespan of individuals infected with the human immunodeficiency virus (HIV, the causative agent of AIDS). Nucleoside reverse transcriptase inhibitors (NRTIs) were the first drugs to be used clinically for the treatment of HIV and remain an essential component of current treatment methods. This research focuses on the design and synthesis of novel NRTIs to more effectively treat the virus and prevent progression to full-blown AIDS. [unreadable] [unreadable] [unreadable]